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Consortium Links Two Loci to Major Depressive Disorder

NEW YORK (GenomeWeb) – An international team of researchers has linked two loci to major depressive disorder.

While a number of previous studies have searched for variants associated with depression, the CONVERGE consortium, led by the University of Oxford's Jonathan Flint, said that no loci actually have been robustly linked to major depressive disorder. This, the team added, could be due to phenotypic and etiologic heterogeneity of the condition, which they sought to overcome by focusing on a patient population in which known sources of phenotypic and genetic heterogeneity were minimized.

Using low-coverage, whole-genome sequencing, the research team scanned the genomes of more than 5,300 Han Chinese women with recurrent major depressive disorder and controls to uncover two loci, one near SIRT1 and one in an intron of LHPP, associated with the condition, as the consortium reported today in Nature. Then, focusing on a more severe form of the condition, melancholia, the team found an increased genetic signal at SIRT1.

"We attribute the discovery and replication of two SNPs associated with MDD in the CONVERGE cohort to the recruitment of cases who were probably more homogeneous and more severely impaired than those collected in previous studies from Western cultures," Flint and his colleague wrote in their paper.

The consortium recruited 11,670 Han Chinese women with recurrent major depressive disorder from 58 different hospitals in China and controls undergoing minor surgical procedures at local hospitals. After quality control filtering, there were 5,503 cases and 5,337 controls that the researchers sequenced to a mean 1.7X depth.

They compared the genotypes garnered from this low-coverage sequencing to those called using 10X coverage sequence, genotyping arrays, and a mass spec-based approach. The mean concordance across all sites was 98.1 percent, the researchers reported, for the low- and high-coverage sequencing, and 98.0 percent overall between the various platforms.

Through a genetic association analysis, the team homed in on two loci with genome-wide significance: one located at 5' of the sirtuin1 (SIRT1) gene and one in an intron of the phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) gene, both on chromosome 10.

The researchers then assessed the imputed genotypes at 12 SNPs by re-genotyping these samples and confirmed their association with major depression using Agena Bioscience's MassARRAY system.

They further replicated this finding in a separate cohort of 3,231 cases and 3,186 controls of both sexes.

However, the researchers failed to replicate their top SNPs using the results from the Psychiatric Genomics Consortium, a mega-analysis of European studies. They noted, though, that variants at their strongest SNPs are rare in European populations.

By focusing on a subset of patients with melancholia, the researchers sought to determine whether their discovery of depression-related loci was due to the inclusion of patients with a severe and more heritable form of the disease.

In their 4,509 cases with melancholia and 5,337 controls, the researchers found that the same two loci passed genome-wide significance for the disease. Further, they noted that the strength of the association between the loci near SIRT1 was nearly two orders of magnitude higher.

SIRT1, the researchers noted, is involved in mitochondrial biogenesis. In conjunction with their finding that major depression is also linked with increased amounts of mitochondrial DNA indicates "an unexpected origin" for some symptoms of the condition.

The researchers added that depression is likely polygenic and more loci remain to be uncovered.